The studies outlined in this proposal are designed to develop a better understanding of the determinants of efficient ribozyme cleavage of HIV-1 RNAs. The specific aims of this proposal are: 1) To determine if models of the secondary structure of HIV-1 mRNAs predict efficient ribozyme cleavage of specific sites within these RNAs. 2) To determine if intracellular localization of target RNAs affects ribozyme activity. and 3) To determine if intracellular localization of ribozymes affects ribozyme catalytic activity. Although the research plan outlined in this proposal is designed to evaluate the factors that affect ribozyme-substrate interactions in cells, these studies are expected to contribute to a better understanding of intracellular RNA-RNA interactions in general and to help in the application of other RNA based technologies such as RNA ligands and antisense RNAs. In addition to the development of more effective anti-HIV therapies, the studies in this proposal may be applicable to the development of RNA-based therapies of other diseases in which modification or inhibition of gene expression could alter disease progression.